Utilization, user characteristics, and adverse outcomes of insulin glargine originators and follow-on drug in patients with diabetes in the United States

BACKGROUND: The first follow-on drug (Basaglar) of the originator insulin glargine (Lantus), a long-acting insulin for treatment of type 1 and type 2 diabetes mellitus (T1DM, T2DM), was approved in 2015 in the United States. Information on the uptake, user characteristics, and outcomes of follow-on insulin remains sparse. OBJECTIVE: To describe the utilization, user characteristics, and health outcomes of the follow-on insulin glargine and insulin glargine originators in a large, distributed network of primarily commercially insured patients in the United States. METHODS: We used health care claims data in the US Food and Drug Administration’s Sentinel common data model format across 5 research partners in the Biologics & Biosimilars Collective Intelligence Consortium distributed research network. Sentinel analytic tools were used to identify adult users of insulin glargine between January 1, 2011, and February 28, 2021, and describe patient demographics, baseline clinical characteristics, and adverse health events among users of the originators and the follow-on drug, stratified by diabetes type. RESULTS: We identified 508,438 users of originator drugs and 63,199 users of the follow-on drug. The proportions of the follow-on drug users among total insulin glargine users were 9.1% (n = 7,070) for T1DM and 11.4% (n=56,129) for T2DM. Follow-on use rose from 8.2% in 2017 to 24.8% in 2020, accompanied by a steady decrease in the use of originator drugs. Demographics of the users of the originators and follow-on drug were similar among the T1DM and T2DM groups. Overall, follow-on users had poorer baseline health profile and higher proportions of episodes with adverse events in the follow-up. CONCLUSIONS: We found evidence of increased uptake of the follow-on drug relative to the originator products in the post-2016 period. The differences in the base-line clinical characteristics between users of the originator products and the follow-on drug and their relationship with health outcomes merit further research.


METHODS:
We used health care claims data in the US Food and Drug Administration's Sentinel common data model format across 5 research partners in the Biologics & Biosimilars Collective Intelligence Consortium distributed research network. Sentinel analytic tools were used to identify adult users of insulin glargine between January 1, 2011, and February 28, 2021, and describe patient demographics, baseline clinical characteristics, and adverse health events among users of the originators and the follow-on drug, stratified by diabetes type.

RESULTS:
We identified 508,438 users of originator drugs and 63,199 users of the follow-on drug. The proportions of the follow-on drug users among total insulin glargine users were 9.1% (n = 7,070) for T1DM and 11.4% (n = 56,129) for T2DM. Follow-on

Plain language summary
We studied health care insurance claims from 508,438 people who used the insulin glargine originator and 63,199 who used the insulin glargine follow-on product. The number of people using the follow-on drug rose from 8.2% in 2017 to 24.8% in 2020. People using the follow-on product were sicker to begin with. They also had more adverse events during treatment. More research is needed to better understand these outcomes.

Implications for managed care pharmacy
Managed care pharmacies can optimize the use of the follow-on insulin by investigating and acting on any impediments to its uptake in a timely manner. By describing the variations in uptake of the follow-on product by diabetes type and baseline clinical characteristics, this study provides useful insights into potential areas of improvement and strategies for future research. effectiveness of biologic drugs, including biosimilars, in the United States. The BBCIC DRN consists of administrative claims data for approximately 95 million patient-years from 5 research partners, including 2 large national health insurers (CVS Health Clinical Trial Services [Aetna] and HealthCore, Inc. (Elevance Health) [Anthem]) and 3 regional health insurers or integrated health care delivery systems (Harvard Pilgrim Health Care, HealthPartners, and Kaiser Permanente of Washington). These research partners participate in the FDA's Sentinel System, enabling the BBCIC to leverage the curated data in the Sentinel Common Data Model and the data standardization and analytic tools of the Sentinel System for conducting distributed analyses. [9][10][11] We identified adult (aged ≥ 18 years) patients with T1DM and T2DM receiving an insulin glargine originator or follow-on drug between January 1, 2011, and February 28, 2021, in the BBCIC DRN. Administrative health care claims data from 5 research partners contributing to the BBCIC DRN during the query period were used. Only 2011-2018 data were full-year data for all research partners. Among the 5 research partners, 1 provided data through part of 2021, 1 through 2020, 1 through part of 2020, and 2 through part of 2019. As such, the proportions of users and episodes are derived from a smaller pool of patients in 2019 and 2020. Insulin glargine drugs of interest included 3 originators (Lantus, Toujeo, Soliqua) and the follow-on drug (Basaglar).
The type of diabetes was determined by the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and ICD-10-CM diagnosis codes for T1DM and T2DM appearing in any position in claims from any care setting throughout each patient's enrollment history (see Supplementary Table 1 for the lists of diagnosis codes for T1DM and T2DM, available in online article). If patients had codes for both T1DM and T2DM in their history, we used an algorithm to categorize them into the appropriate cohort. Specifically, if 50% or more of the codes were T2DM vs T1DM, the patient was assigned to T2DM. If the ratio was less than 50%, the patient was assigned to T1DM. This algorithm performed better at determining diabetes type in a validation study using electronic health record data in terms of overall sensitivity and positive predictive value than the algorithms that used T1DM or T2DM diagnosis codes but did not use the ratio of the frequencies of these codes. 12 Drugs of interest were identified using National Drug Code numbers in the outpatient pharmacy claims. Each dispensing of an insulin of interest was considered an episode, with the date of dispensing serving as the index date. Patients were required to be enrolled in medical and pharmacy coverage for at least 183 days prior to an index date ("baseline period"), with no gap in enrollment of longer than 45 days Insulin was first used to treat a patient with diabetes in 1922; it has since remained the mainstay drug for the treatment of type 1 diabetes mellitus (T1DM) and advanced type 2 diabetes mellitus (T2DM). 1 The rapidly escalating prices of insulin in the United States are a cause for concern for policymakers and patients alike. 2 The national cost attributed to insulin use for diabetes care in the United States was estimated at $15 billion in 2017. 1 Many patients are forced to delay filling or completely forego insulin prescriptions owing to the high out-of-pocket costs. 3,4 Biosimilars are drugs that are highly similar and have no clinically meaningful differences to a reference biologic. 5 Though insulin is a biologic, its approval predated the creation of the approval process for biologics under the Public Health Service Act. As a result, insulin was regulated as a small molecule until 2020, 1,6 and as such, it was not initially possible to designate an insulin "reference" biologic. To circumvent this regulatory inconsistency, the follow-on pathway was used, which allows applicants to seek approval for a drug based on structural similarities with an originator product, without contesting for the status of being interchangeable with the originator product. 6 Follow-on products have the potential to improve patient care by driving down costs and improving access to biologics. Lantus (insulin glargine approved by the US Food and Drug Administration [FDA] in April 2000) is the original long-acting insulin product and is widely prescribed in the United States. Other insulin glargine products include Toujeo, a high-concentration drug, and Soliqua, a combination of insulin glargine and a glucagonlike peptide-1 receptor agonist. Basaglar, the first follow-on insulin glargine, was approved by the FDA in December 2015 but was not available to patients until December 2016. 7,8 Ensuring that a treatment alternative has a positive impact on patient care requires close monitoring of its uptake, as well as identifying, monitoring, and addressing any potential concerns pertaining to its safety and efficacy. However, information on the uptake and real-world health outcomes of follow-on insulin remains sparse. This report fills these knowledge gaps by describing the utilization, user characteristics, and health outcomes of the follow-on insulin glargine and insulin glargine originators in a large, distributed network of commercially insured patients in the United States.

Methods
We used data from the distributed research network (DRN) of the Biologics and Biosimilars Collective Intelligence Consortium (BBCIC)-a nonprofit, multistakeholder research consortium for investigating real-world safety and The demographic characteristics of the users of the originators and the follow-on drug were similar in the 2 groups. However, the mean Charlson/Elixhauser combined comorbidity scores (T1DM group, 0.5 for originator drugs vs 0.8 for the follow-on drug; T2DM group, 1.0 for originator drugs vs 1.4 for the follow-on drug) and the proportions of episodes with diabetic neuropathy (T1DM group, 9.5% for originator drugs vs 10.4% for the follow-on drug; T2DM group, 19.4% for the originator drugs vs 24.0% for the follow-on drug), diabetic retinopathy (T1DM group, 13.3% for originator drugs vs 15.1% for the follow-on drug; T2DM group, 11.8% for the originator drugs vs 13.6% for the followon drug), and nephropathy (T1DM group, 3.6% for originator drugs vs 4.0% for the follow-on drug; T2DM group, 12.9% for the originator drugs vs 14.8% for the follow-on drug) in the baseline were higher for episodes of the follow-on drug in both groups, with more marked differences in absolute numbers seen in the T2DM group. Higher proportions among the follow-on drug episodes were observed for hyperglycemia (T1DM group, 1.7% for originator drugs vs 3.3% for the follow-on drug; T2DM group, 2.4% for the originator drugs vs 3.9% for the follow-on drug) and diabetic ketoacidosis (T1DM group, 2.5% for originator drugs vs 3.9% for the follow-on drug; T2DM group, 2.3% for the originator drugs vs 3.9% for the follow-on drug) during the 183-day follow-up.

Discussion
In this longitudinal study of utilization of insulin glargine, we found evidence of increased uptake of the follow-on drug relative to the originator products after 2016, both among patients with T1DM and T2DM. This study improved on previous research into the uptake of the follow-on drug by using more current data and using an algorithm that has been validated to more accurately identify patients with T1DM and T2DM. 13 With respect to the counts of users and episodes per thousand patients, there was an upward trend in the use of the follow-on drug in the T2DM group through 2020, whereas utilization stabilized in the T1DM group post-2018.
The observed patterns may be related to changes in pharmacy benefit plans over time, the intrinsic differences between the T1DM and T2DM patient populations, and the rank order of antidiabetic medications used to treat the 2 types of diabetes. Although insulin is the first line of treatment for patients with T1DM, who are generally younger at the time of diagnosis, insulin use is reserved for patients with advanced T2DM who might have received multiple treatments before insulin was initiated. Accordingly, we expect the T2DM group to have a greater proportion of during that period. We excluded patients with diagnosis or procedure codes related to any of the following adverse health events in the inpatient or emergency department setting during the baseline period: diabetic ketoacidosis, hypoglycemia, and major adverse cardiac event, including acute myocardial infarction, acute coronary syndrome, ischemic heart disease, unstable angina, stroke, cardiac or carotid revascularization procedure, and heart failure. Demographic characteristics were assessed on the index date, and baseline clinical characteristics were assessed in the baseline period. The abovementioned adverse health events were assessed within a period of 183 days following the index date. A comprehensive list of codes used in this analysis can be retrieved from https://www.bbcic.org.
We measured the overall and annual numbers of prevalent users and use episodes of the originators and the follow-on drug among patients with T1DM and T2DM. Additionally, we described the patient demographics, baseline clinical characteristics, and post-index adverse health events among the users of the originators and the follow-on drug separately, stratified by diabetes type. We used the publicly available Sentinel System analytic toolkit (Cohort ID and Descriptive Analysis v10.3.2) to conduct distributed analyses at each research partner site and aggregated the results across the sites. Institutional review boards for the participating research partners determined that this work does not meet the definition of human-subjects research.

Results
We identified 508,438 users (5,544,116 episodes) of originator drugs and 63,199 users (341,618 episodes) of the follow-on drug among all patients with diabetes. Overall, the proportions of the follow-on drug users among total insulin glargine users were 9.1% (n = 7,070) in the T1DM group and 11.4% (n = 56,129) in the T2DM group. Utilization of the follow-on drug was first observed in 2016. The proportion of the follow-on drug users among total insulin glargine users increased from 8.2% in 2017 to 24.8% in 2020. Table 1 presents the baseline characteristics and post-index health outcomes of insulin glargine users and the annual counts of prevalent users and episodes of insulin glargine. The use of the follow-on drug plateaued in the years following 2018 in the T1DM group but increased more steadily through the end of the study period in the T2DM group. Correspondingly, there was a steady decline in the number of users and episodes of the originator drugs in the years following 2016, both among T1DM and T2DM patients. Similar trends were observed in the year-wise breakout of users and episodes of insulin glargine per thousand patients with T1DM and T2DM (Figure 1). Use of insulin glargine originators and follow-on drug in patients with diabetes in the US Vol Glargine   TABLE 1 follow-up. These patients could initially be at higher risk of hyperglycemia until the dose is stabilized. Nevertheless, efficacy and safety of newly approved drugs are important considerations that need to be continuously monitored through postmarketing surveillance. An amendment to the Public Health Service Act by the Patient Protection and Affordable Care Act in March 2020 paved the way for the development of biosimilar insulin glargine products. Since then, the FDA has approved 2 biosimilar insulin glargine products-Semglee and Rezvoglarwhich are deemed interchangeable with Lantus, and more products are in the pipeline. 15 The introduction of follow-on and biosimilar insulin glargine products has the potential to improve diabetes care by allowing for price competition and broadening of treatment choices. For this potential to be realized, it is imperative that any potential impediments to these product's adoption be identified and redressed in a timely manner. This study provides important insights for future research in this area by highlighting the trends and variations in uptake, baseline clinical characteristics, and health outcomes of the follow-on insulin glargine and the originator drugs in patients with T1DM and T2DM.

LIMITATIONS
There are some limitations to this study. The BBCIC DRN comprises administrative claims data of primarily commercially insured individuals. These findings may not be generalizable to other population groups, such as Medicare fee-for-service or Medicaid enrollees. As data from 2021 were incomplete, we were not able to analyze trends in utilization beyond 2020. Information on person-time was incident insulin users among all insulin users than the T1DM group. It could be that physicians are less likely to prescribe the follow-on drug to people with adequately controlled diabetes who are longer-term users of an originator insulin. 14 Furthermore, patients who have been using an originator insulin since a young age would be more likely to possess brand loyalty than older, advanced patients with more diverse treatment histories. Future research should examine the potential factors associated with the uptake of the follow-on drug, including incident vs prevalent use of insulin, the duration of treatment with insulin, adequacy of diabetes control in the baseline, device compatibility with the follow-on drug, price elasticity for the follow-on drug, patients' and prescribers' conceptual understanding of the follow-on drug and their attitudes toward switching, and differential pricing, reimbursement, and formulary placement of the follow-on drug.
Apart from major adverse cardiac events, we observed higher proportions of episodes with post-index adverse events among users of the follow-on agent. This is expected given the poorer baseline health profile of the followon drug users. Furthermore, our definition of originator drugs included not only Lantus, the reference product for Basaglar, but also other insulin glargine-based products approved before Basaglar, including a high-concentration product (Toujeo) and a combination product (Soliqua). This broader definition of originator products could have impacted the analyses of adverse events. For instance, to minimize the risk of hypoglycemia, clinicians might reduce the daily dose of insulin when switching from Toujeo to a lower-concentration product and titrate the dose on

FIGURE 1
Users and Episodes of Insulin  not collected; hence, incidence rates of adverse events could not be calculated. Also, the adverse event rates were crude and not adjusted for potential differences in baseline patient characteristics. This is purely a descriptive work aimed at informing future analyses. We did not evaluate switching and adherence patterns, and the study design did not lend itself to testing of statistical significance. Finally, there is the possibility of misclassification in identifying drug exposures and clinical characteristics through administrative claims data.

Conclusions
In this large, primarily commercially insured population, we found evidence of increased uptake of the follow-on drug relative to the originator products after the follow-on drug became available. There was an upward trend in the use of the followon drug in the T2DM group through 2020, whereas utilization stabilized in the T1DM group post-2018. Episodes of the follow-on drug had higher mean Charlson/Elixhauser combined comorbidity scores and higher proportions of nephropathy, diabetic neuropathy, and diabetic retinopathy at baseline than episodes of the originator products. This finding could be related to the higher proportions of adverse events observed among episodes of the follow-on drug.

DISCLOSURES
Sengwee Toh consults for Pfizer, Inc., and TriNetX, LLC. This study was funded by the BBCIC.